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A VIPoma is an endocrine tumor, usually originating in the pancreas, which produces a vasoactive intestinal peptide and is believed to cause profound cardiovascular and electrolyte changes with vasodilatory hypotension, watery diarrhea, hypokalemia, and dehydration.

VACTERL association
Van der Woude syndrome
Van Goethem syndrome
Varicella Zoster
Variegate porphyria
Vasovagal syncope
VATER association
Velocardiofacial syndrome
Ventricular septal defect
Viral hemorrhagic fever
Vitamin B12 Deficiency
VLCAD deficiency
Von Gierke disease
Von Hippel-Lindau disease
Von Recklinghausen disease
Von Willebrand disease


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Novel p53 mutation in a malignant tumor secreting vasoactive intestinal peptide
From Archives of Pathology & Laboratory Medicine, 2/1/97 by Henry J Lin

* Objective.-To assess involvement of p53 mutations in development of pancreatic endocrine tumors.

Design.-Survey of sporadic pancreatic endocrine tumors.

Setting-Hospital referral centers, mainly in the Los Angeles, Calif, area.

Patients.-We obtained fresh surgical specimens from 25 patients (convenience sample) with no family history of endocrine tumors and no evidence of multiple endocrine neoplasia 1 or von Hippel-Lindau disease. Preoperative tests included serum peptide analysis.

Main Outcome Measures.-DNA was prepared from tu

mor specimens. We screened exons 5 through 8 of the p53 gene using single-strand conformation polymorphism analysis, followed by DNA sequencing when a variant was detected.

Results.-A three-base deletion mutation (codon 239) was found in one malignant tumor secreting vasoactive intestinal peptide.

Conclusions.-p53 appears to have a limited role in development of pancreatic endocrine tumors. However, evidence from one of our patients suggests it may be involved in tumor progression in uncommon cases.

(Arch Pathol Lab Med. 1997;121:125-128)

Pancreatic endocrine tumors are uncommon islet cell neoplasms that secrete pancreatic polypeptides, such as insulin, gastrin, and other hormones. The tumors can occur sporadically or as part of familial syndromes. Clinical behavior varies from benign to highly malignant, and management is aimed at tumor detection before metastases occur. Presence or absence of metastases at the time of diagnosis is used as a prognostic indicator, owing to lack of reliable histologic or other markers of malignancy.1


Tumor 43T was from a man who presented at age 53 years with a 9-month history of watery diarrhea (20 stools and up to 7-8 liters per day) and a 20-kg weight loss. The patient's serum vasoactive intestinal peptide (VIP) level was 500 pg/mL (reference,


Only tumor 43T contained a detectable p53 mutation. Polymerase chain reaction products from the tumor showed deletion of codon 239 (AAC, for asparagine) in four independent plasmid clones. The mutation was confirmed by showing loss of an AlwNI restriction enzyme site in uncloned polymerase chain reaction products (Fig 2). Southern blotting with probes that flank the p53 gene showed a heterozygous pattern for both tumor and control DNA (not shown), consistent with no large deletion at these loci (D17S28 [pYNH37.3] and D17S30 [pYNZ22]). Polymerase chain reaction and AlwNI digestion of DNA from a paraffin-embedded section of the primary tumor showed loss of the restriction site, indicating that the primary tumor also contained the mutation (not shown).

Loss of asparagine at position 239 (Asn2,3,9) appears to be a novel mutation. Codon 239 is not conserved among species, and only 18 (0.47%) missense mutations in this codon have been reported among 3804 p53 mutations.6 Asn2,3,9 is part of the DNA-binding loop formed by residues 236 through 251.7 In the loop, serine (position 241) and arginine (position 248) bind to DNA. Two cysteine side chains (positions 238 and 242) are zinc ligands. Glycine (position 245) is a mutation hot spot and forms hydrogen bonds with cysteine (position 242) and arginine (position 249). Thus, shortening this peptide loop is apt to alter p53 function by shifting DNA-binding and zinc-binding side chains. Loss of Asn239 may be a gain of function mutation as observed for other p53 mutations, like the arginine to tryptophan substitution at position 248.8 The mutation is compatible with a palindrome mechanism for formation of deletions, a model that may account for 5% of p53 deletions and insertions.9

Our screening could have missed some mutations, because analysis of only exons 5 through 8 can underestimate the frequency of p53 mutations by 20% or more, depending on the tumor type.3 Also, SSCP analysis detects only 70% to 80% of single-base mutations in DNA fragments of 212 bases or less.10

Little is known of genetic events in development of pancreatic endocrine tumors. Earlier work gave evidence for inactivation of a tumor suppressor gene at chromosome region 11q13 in 30% to 40% of tumors.ll Another study suggested amplification of the Her-2/neu proto-oncogene in gastrinomas, and one tumor had a p53 mutation in codon 273.lz A third study found no p53 mutation among 11 pancreatic endocrine tumors (nine adenomas, two carcinomas).3 Thus, these tumors, like other endocrine tumors, have a low frequency of p53 mutations. The low frequency may reflect early diagnosis and lack of p53 involvement at early stages.

Molecular studies should be useful in defining steps in pancreatic endocrine tumorigenesis and identifying genetic differences between benign and malignant forms. However, such studies can be difficult, because the tumors are fairly rare. Yearly incidences for insulinomas and gastrinomas are roughly four per million.l Our material represents one of the largest collections of pancreatic endocrine tumors available. The lack of a detectable mutation among 13 tumors with no metastasis is consistent with little or no role for p53 in early tumors. A mutation in one of seven malignant tumors may be compatible with p53 involvement in some metastatic cases.

This work was supported by the Cancer Research Foundation of America, a March of Dimes Basil O'Connor Award, American Cancer Society Institutional Grant IN/IRG 131N to the Jonsson Comprehensive Cancer Center at the University of California at Los Angeles, the University of California Cancer Research Coordinating Committee, the Harbor Collegium at Harbor-UCLA Medical Center, and the Peg Liddle Fund at Eisenhower Medical Center, Rancho Mirage, Calif (Dr Lin).

Chun-Ya Han, Andrew D. Louie, and Gordon T. Sakamoto provided technical assistance. Nicola Basso, MD (University of Rome "La Sapienza," Italy), Barry Mann, MD (St John's Medical Center, Los Angeles, Calif), J. Margolis, MD (Kaiser Permanente, Panorama City, Calif), Robert Rudek, MD (Kaiser Permanente, Riverside, Calif), Bruce Stabile, MD (Harbor-UCLA Medical Center, Torrance, Calif), and Cheryl Wessen, MD (Brooke Army Medical Center, San Antonio, Tex) provided some of the tumor specimens. Michael Hurwitz, MD, Carey L. Johnson, MD, and Ghassan Samara, MD, provided helpful discussion.


1. Delcore R, Friesen SR. Gastrointestinal neuroendocrine tumors. J Am Coll Surg. 1994;178:187-211.

2. Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250: 1233-1238.

3. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855-4878.

4. Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature.1991;350: 427-428.

5. Mekhjian HS, O'Dorisio TM. VIPoma syndrome. Semin Oncol. 1987;14: 282-291.

6. Hollstein M, Rice K, Greenblatt MS, et al. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 1994;22:35513555.

7. Cho Y, Gorina S, Jeffrey PD, Pavletich NP. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994;265:346-355.

8. Dittmer D, Pati S, Zambetti G, et al. Gain of function mutations in p53. Nat Genet.1993;4:42-46.

9. Greenblatt MS, Grollman AP, Harris CC. Deletions and insertions in the p53 tumor suppressor gene in human cancers: confirmation of the DNA polymerase slippage/misalignment model. Cancer Res. 1996;56:2130-2136.

10. Sheffield VC, Beck JS, Kwitek AE, Sandstrom DW, Stone EM. The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions. Genomics.1993;16:325-332.

11. Eubanks PJ, Sawicki MP, Samara GJ, et al. Putative tumor-suppressor gene on chromosome 11 is important in sporadic endocrine tumor formation. Am J Surg. 1994;167:180-185.

12. Evers BM, Rady PL, Sandoval K, et al. Gastrinomas demonstrate amplification of the HER-2/neu proto-oncogene. Ann Surg. 1994;219:596-604. 13. Yoshimoto K, Iwahana H, Fukuda A, Sano T, Saito S, Itakura M. Role of p53 mutations in endocrine tumorigenesis: mutation detection by polymerase chain reaction-single strand conformation polymorphism. Cancer Res.1992;52: 5061-5064.

Accepted for publication September 24, 1996.

From the Departments of Pediatrics (Dr Lin) and Pathology (Drs French and Wan), Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance; Department of Surgery, West Los Angeles VA Medical Center (Drs Passaro and Sawicki), UCLA School of Medicine; and Department of Pathology, Harborview Medical Center and University of Washington, Seattle (Dr Reichenbach). Reprint requests to Division of Medical Genetics, E4, Harbor-UCLA Medical Center, 1124 W Carson St, Torrance, CA 90502 (Dr Lin).

Copyright College of American Pathologists Feb 1997
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